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1.
Mol Neurobiol ; 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34984583

RESUMO

Parkinson's disease (PD) is an incurable neurodegenerative disease characterized by aggregation of pathological alpha-synuclein (α-syn) and loss of dopaminergic neuron in the substantia nigra. Inhibition of phosphorylation of the α-syn has been shown to mediate alleviation of PD-related pathology. Protein phosphatase 2A (PP2A), an important serine/threonine phosphatase, plays an essential role in catalyzing dephosphorylation of the α-syn. Here, we identified and validated cancerous inhibitor of PP2A (CIP2A), as a potential diagnostic biomarker for PD. Our data showed that plasma CIP2A concentrations in PD patients were significantly lower compared to age- and sex-matched controls, 1.721 (1.435-2.428) ng/ml vs 3.051(2.36-5.475) ng/ml, p < 0.0001. The area under the curve of the plasma CIP2A in distinguishing PD from the age- and sex-matched controls was 0.776. In addition, we evaluated the role of CIP2A in PD-related pathogenesis in PD cellular and MPTP-induced mouse model. The results demonstrated that CIP2A is upregulated in PD cellular and MPTP-induced mouse models. Besides, suppression of the CIP2A expression alleviates rotenone induced aggregation of the α-syn as well as phosphorylation of the α-syn in SH-SY5Y cells, which is associated with increased PP2A activity. Taken together, our data demonstrated that CIP2A plays an essential role in the mechanisms related to PD development and might be a novel PD biomarker.

2.
Front Immunol ; 12: 719807, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34691027

RESUMO

According to emerging studies, the excessive activation of microglia and the subsequent release of pro-inflammatory cytokines play important roles in the pathogenesis and progression of Parkinson's disease (PD). However, the exact mechanisms governing chronic neuroinflammation remain elusive. Findings demonstrate an elevated level of NLRP3 inflammasome in activated microglia in the substantia nigra of PD patients. Activated NLRP3 inflammasome aggravates the pathology and accelerates the progression of neurodegenerative diseases. Abnormal protein aggregation of α-synuclein (α-syn), a pathologically relevant protein of PD, were reported to activate the NLRP3 inflammasome of microglia through interaction with toll-like receptors (TLRs). This eventually releases pro-inflammatory cytokines through the translocation of nuclear factor kappa-B (NF-κB) and causes an impairment of mitochondria, thus damaging the dopaminergic neurons. Currently, therapeutic drugs for PD are primarily aimed at providing relief from its clinical symptoms, and there are no well-established strategies to halt or reverse this disease. In this review, we aimed to update existing knowledge on the role of the α-syn/TLRs/NF-κB/NLRP3 inflammasome axis and microglial activation in PD. In addition, this review summarizes recent progress on the α-syn/TLRs/NF-κB/NLRP3 inflammasome axis of microglia as a potential target for PD treatment by inhibiting microglial activation.

3.
Brain ; 144(7): 2024-2037, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-33792662

RESUMO

Increasing evidence suggests that microglial activation is strongly linked to the initiation and progression of Parkinson's disease. Cell-to-cell propagation of α-synuclein pathology is a highlighted feature of Parkinson's disease, and the focus of such research has been primarily on neurons. However, recent studies as well as the data contained herein suggest that microglia, the primary phagocytes in the brain, play a direct role in the spread of α-synuclein pathology. Recent data revealed that plasma exosomes derived from Parkinson's disease patients (PD-EXO) carry pathological α-synuclein and target microglia preferentially. Hence, PD-EXO are likely a key tool for investigating the role of microglia in α-synuclein transmission. We showed that intrastriatal injection of PD-EXO resulted in the propagation of exosomal α-synuclein from microglia to neurons following microglia activation. Toll-like receptor 2 (TLR2) in microglia was activated by exosomal α-synuclein and acted as a crucial mediator of PD-EXO-induced microglial activation. Additionally, partial microglia depletion resulted in a significant decrease of exogenous α-synuclein in the substantia nigra. Furthermore, exosomal α-synuclein internalization was initiated by binding to TLR2 of microglia. Excessive α-synuclein phagocytosis may induce the inflammatory responses of microglia and provide the seed for microglia-to-neuron transmission. Consistently, TLR2 silencing in microglia mitigated α-synuclein pathology in vivo. Overall, the present data support the idea that the interaction of exosomal α-synuclein and microglial TLR2 contribute to excessive α-synuclein phagocytosis and microglial activation, which lead to the further propagation and spread of α-synuclein pathology, thereby highlighting the pivotal roles of reactive microglia in α-synuclein transmission.


Assuntos
Exossomos/metabolismo , Microglia/metabolismo , Doença de Parkinson/metabolismo , Receptor 2 Toll-Like/metabolismo , alfa-Sinucleína/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/patologia , Doença de Parkinson/patologia , Ratos , Ratos Sprague-Dawley
4.
BMC Infect Dis ; 21(1): 110, 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33485297

RESUMO

BACKGROUND: Compelling evidence indicates that status epilepticus is a prevalent cause of rhabdomyolysis. However, cases of rhabdomyolysis induced by a single seizure accompanied by viral encephalitis are rarely reported. Herein, we present a case of adult Herpes Simplex Encephalitis complicated with rhabdomyolysis. CASE PRESENTATION: A 32-year-old male was patient presented with fever accompanied by episodes of convulsions, myalgia, and oliguria, which exacerbated the delirium. Routine blood examination showed impaired kidney function and elevated myoglobin (Mb) and creatine phosphokinase (CK) levels. MRI scanning revealed a damaged frontotemporal lobe and limbic system. In addition, herpes simplex virus (HSV) pathogen was identified in the cerebrospinal fluid thus indicating HSV infection. Therefore, a diagnosis of rhabdomyolysis triggered by HSV infection accompanied by epilepsy was made. Notably, the patient recovered well after early intervention and treatment. CONCLUSION: The case presented here calls for careful analysis of rhabdomyolysis cases with unknown causes, minor seizures, and without status epilepticus. This case also indicates that HSV virus infection might contribute to the rhabdomyolysis.


Assuntos
Encefalite por Herpes Simples/complicações , Encefalite por Herpes Simples/diagnóstico , Rabdomiólise/diagnóstico , Rabdomiólise/etiologia , Adulto , Febre/diagnóstico , Febre/etiologia , Febre/patologia , Febre/fisiopatologia , Humanos , Masculino , Rabdomiólise/patologia , Rabdomiólise/fisiopatologia , Convulsões/diagnóstico , Convulsões/etiologia , Convulsões/patologia , Convulsões/fisiopatologia , Simplexvirus/isolamento & purificação
5.
Int J Neurosci ; 131(7): 674-680, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32253955

RESUMO

BACKGROUND: Parkinson's disease (PD) is a common progressive neurodegenerative disorder. Up to now, several single-nucleotide polymorphisms (SNPs) located in virulence gene sites have been reported linked to PD. Candidate gene association studies and genome-wide association studies have identified rs3129882, rs4248166 in HLA-DRA and rs34372695 in SYT11 as risk factors for familial or sporadic PD. However, the association between variants of HLA-DRA, SYT11 and PD are still controversial, especially in the Central Chinese population. We here performed a case-control study to investigate whether HLA-DRA and SYT11 genes could predispose to sporadic PD in the Chinese population. METHODS: We investigate 486 PD patients and 457 age- and sex-matched controls from Central China to assess this association. RESULTS: In the allele model, the odds ratio (OR) result of rs3129882 was 0.905 (p = 0.287). Moreover, no significant difference was observed in the association between rs424816 (OR = 0.864, p = 0.106) and rs34372695 (p = 1.0) with PD risk. Genotypic analysis in SNP rs3129882, rs4248166 and rs34372695 indicated no significant association with PD. Subgroup analysis of our data showed age-onset and gender were not associated with either genotype or minor allele frequencies of rs3129882 and rs4248166. Moreover, the negative results were also observed in a meta-analysis of studies of rs3129882 from mainland China and Taiwanese population. CONCLUSIONS: Our results reveal that rs3129882, rs4248166 and rs34372695 do not confer significant risks for sporadic PD in the Central Chinese population.

6.
Aging (Albany NY) ; 12(19): 18853-18865, 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33052140

RESUMO

The outbreak of coronavirus disease 2019 (COVID-19) has become a world-wide emergency. The severity of COVID-19 is highly correlated with its mortality rate. We aimed to disclose the clinical characteristics and prognostic factors of COVID-19 patients who developed severe COVID-19. The study enrolled cases (no=1848) with mild or moderate type of COVID-19 in Fangcang shelter hospital of Jianghan. A total of 56 patients progressed from mild or moderate to severe. We used least absolute shrinkage and selection operator regression model to select prognostic factors for this model. The case-severity rate was 3.6% in the shelter hospital. They were all symptomatic at admission. Fever, cough, and fatigue were the most common symptoms. Hypertension, diabetes and coronary heart diseases were common co-morbidities. Predictors contained in the prediction nomogram included fever, distribution of peak temperature (>38°C), myalgia or arthralgia and distribution of C-reactive protein (≥10 mg per L). The distribution of peak temperature (>38°C) on set, myalgia or arthralgia and C-reactive protein (≥10 mg per L) were the prognostic factors to identify the progression of COVID-19 patients with mild or moderate type. Early attention to these risk factors will help alleviate the progress of the COVID-19.

7.
Sleep Med ; 75: 428-433, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32980664

RESUMO

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is adversely affecting sleep quality and mental health, especially in individuals with chronic disease such as Parkinson's disease (PD). METHODS: We conducted a quantitative study, which included 119 Chinese PD patients who had been treated in an outpatient neurology clinic in Wuhan and 169 age- and sex-matched healthy controls. The questionnaire survey focused on the impact of the COVID-19 pandemic on sleep, mental status, symptoms, and daily life and medical treatment of PD patients. RESULTS: Compared to healthy controls, PD patients had significantly higher scores in both the Pittsburgh Sleep Quality Index (PSQI) (8.13 vs 5.36, p < 0.001) and the Hospital Anxiety and Depression Scale (HADS) -Depression (4.89 vs 3.82, p = 0.022), as well as a higher prevalence of sleep disturbances with PSQI > 5 points (68.9% vs 44.4%, p < 0.001). Sleep disturbance was identified in 68.9% of PD patients. A logistic regression analysis showed that sleep disturbance of PD patients was independently associated with exacerbation of PD symptoms (OR = 3.616, 95%CI= (1.479, 8.844), p = 0.005) and anxiety (OR = 1.379, 95%CI= (1.157, 1.642), p < 0.001). Compared to male PD patients, female ones had higher PSQI scores (9.28 ± 4.41 vs 7.03 ± 4.01, p = 0.009) and anxiety (32.8% vs 0.1%, p = 0.002) and depression prevalence (34.5% vs 11.5%, p = 0.003). CONCLUSION: The findings of the present study emphasize the importance of mental and sleep health interventions in PD patients during the COVID-19 pandemic. Additional attention should be paid to the difficulty encountered by PD patients in seeking medical treatment.


Assuntos
Ansiedade/epidemiologia , COVID-19/psicologia , Depressão/epidemiologia , Pandemias , Doença de Parkinson/epidemiologia , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Idoso , Estudos de Casos e Controles , China , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/psicologia , Pesquisa Qualitativa , Inquéritos e Questionários
8.
Sleep Med ; 72: 1-4, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32502844

RESUMO

OBJECTIVE: To evaluate sleep disturbances of Chinese frontline medical workers (FMW) under the outbreak of coronavirus disease 2019 (COVID-19), and make a comparison with non-FMW. METHODS: The medical workers from multiple hospitals in Hubei Province, China, volunteered to participate in this cross-sectional study. An online questionnaire, including Pittsburgh Sleep Quality Index (PSQI), Athens Insomnia Scale (AIS) and Visual Analogue Scale (VAS), was used to evaluate sleep disturbances and mental status. Sleep disturbances were defined as PSQI>6 points or/and AIS>6 points. We compared the scores of PSQI, AIS, anxiety and depression VAS, as well as prevalence of sleep disturbances between FMW and non-FMW. RESULTS: A total of 1306 subjects (801 FMW and 505 non-FMW) were enrolled. Compared to non-FMW, FMW had significantly higher scores of PSQI (9.3 ± 3.8 vs 7.5 ± 3.7; P < 0.001; Cohen's d = 0.47), AIS (6.9 ± 4.3 vs 5.3 ± 3.8; P < 0.001; Cohen's d = 0.38), anxiety (4.9 ± 2.7 vs 4.3 ± 2.6; P < 0.001; Cohen's d = 0.22) and depression (4.1 ± 2.5 vs 3.6 ± 2.4; P = 0.001; Cohen's d = 0.21), as well as higher prevalence of sleep disturbances according to PSQI > 6 points (78.4% vs 61.0%; relative risk [RR] = 1.29; P < 0.001) and AIS > 6 points (51.7% vs 35.6%; RR = 1.45; P < 0.001). CONCLUSION: FMW have higher prevalence of sleep disturbances and worse sleep quality than non-FMW. Further interventions should be administrated for FMW, aiming to maintain their healthy condition and guarantee their professional performance in the battle against COVID-19.


Assuntos
Ansiedade/epidemiologia , Infecções por Coronavirus/epidemiologia , Depressão/epidemiologia , Pessoal de Saúde/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Adulto , Ansiedade/psicologia , Betacoronavirus , COVID-19 , Estudos de Casos e Controles , China/epidemiologia , Estudos Transversais , Depressão/psicologia , Surtos de Doenças , Feminino , Pessoal de Saúde/psicologia , Humanos , Masculino , Pandemias , Prevalência , SARS-CoV-2 , Fatores Sexuais , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Distúrbios do Início e da Manutenção do Sono/psicologia , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/fisiopatologia , Escala Visual Analógica
9.
J Chem Inf Model ; 59(11): 4833-4843, 2019 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-31657922

RESUMO

Most natural proteins exhibit poor thermostability, which limits their industrial application. Computer-aided rational design is an efficient purpose-oriented method that can improve protein thermostability. Numerous machine-learning-based methods have been designed to predict the changes in protein thermostability induced by mutations. However, all of these methods have certain limitations due to existing mutation coding methods that overlook protein sequence features. Here we propose a method to predict protein thermostability using convolutional neural networks based on an in-depth study of thermostability-related protein properties. This method comprises a three-dimensional coding algorithm, including protein mutation information and a strategy to extract neighboring features at protein mutation sites based on multiscale convolution. The accuracies on the S1615 and S388 data sets, which are widely used for protein thermostability predictions, reached 86.4 and 87%, respectively. The Matthews correlation coefficient was nearly double those produced using other methods. Furthermore, a model was constructed to predict the thermostability of Rhizomucor miehei lipase mutants based on the S3661 data set, a single amino acid mutation data set screened from the ProTherm protein thermodynamics database. Compared with the RIF strategy, which consists of three algorithms, i.e., Rosetta ddg monomer, I Mutant 3.0, and FoldX, the accuracy of the proposed method was higher (75.0 vs 66.7%), and the negative sample resolution was simultaneously enhanced. These results indicate that our prediction method more effectively assessed the protein thermostability and distinguished its features, making it a powerful tool to devise mutations that enhance the thermostability of proteins, particularly enzymes.


Assuntos
Proteínas/química , Animais , Humanos , Modelos Químicos , Modelos Moleculares , Redes Neurais de Computação , Mutação Puntual , Estabilidade Proteica , Proteínas/genética , Temperatura , Termodinâmica
10.
Front Neurol ; 10: 812, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31447756

RESUMO

A 47-year-old HIV-seronegative woman with autoimmune hemolytic anemia (AIHA) was treated with corticosteroids for 8 months. She developed central nervous system dysfunction and was diagnosed with cryptococcal meningitis (CM) after detecting cryptococcus neoformans in the cerebrospinal fluid. The patient's clinical symptoms were worsened and unusual MRI findings of white matter lesions were noticed even after adequate treatment, which were quite unusual compared with typical characteristics of CM. This led us to carry out further investigations. Similar cases have been reported previously in published literature. Combined with clinical symptoms and MRI findings, the most likely diagnosis was Cryptococcal Meningitis-Immune Reconstitution Inflammatory Syndrome. Unfortunately, the patient deteriorated and died of respiratory failure. Cryptococcal Meningitis-Immune Reconstitution Inflammatory Syndrome may have MRI changes during the early onset of the disease (bilateral basal ganglia). We propose that close monitoring of the condition, meticulous MRI follow-up and brain biopsies should be indicated in such cases for treating them actively, so as to avoid worsening of the patients' condition.

11.
J Mol Med (Berl) ; 97(9): 1329-1344, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31302715

RESUMO

Cell-to-cell transport of risk molecules is a highly anticipated pathogenic mechanism in the initiation and progression of various neurodegenerative diseases. Extracellular exosome-mediated neuron to neuron transport of α-synuclein (α-syn) is increasingly recognized as a potential etiologic mechanism in Parkinson's disease (PD). Exosomal inflammation has also been increasingly implicated in PD pathogenesis and could trigger, facilitate, or aggravate disease development. However, these mechanisms have not been verified systematically, especially in vivo. Since serum contains abundant exosomes, the correlation between serum exosomes and PD pathogenesis remains unknown. Here, we show that exosomes from PD patient serum contain more α-syn and inflammatory factors such as IL-1ß and TNF-α than neurological normal controls, eventually cause α-syn, ubiquitin, and P62 aggregation in recipient cells. More importantly, the intravenous or intrastriatal treatment of mice with exosomes from PD patient serum could evoke protein aggregation, trigger dopamine neuron degeneration, induce microglial activation, and cause apomorphine-coaxed rotation and movement defects. All these findings imply the exosome pathway as a new pathogenesis mechanism for PD, and therefore may present new targets for therapeutics. KEY MESSAGES: We have presented the evidence for a relationship between PD (Parkinson's disease) patients' serum exosomes and pathogenesis. PD patients' serum-derived exosomes could induce α-syn, ubiquitin and P62 aggregation in recipient cells. Intravenous or intrastriatal treatments of mice with PD exosomes were able to recapitulate the molecular, cellular and behavioral phenotypes of PD.


Assuntos
Exossomos/patologia , Doença de Parkinson/patologia , Animais , Progressão da Doença , Exossomos/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microglia/metabolismo , Microglia/patologia , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo
12.
Phytomedicine ; 60: 152954, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31130327

RESUMO

BACKGROUND: It is established that natural medicines for Parkinson's disease (PD) provide an antioxidant activity in preventing dopaminergic neurons from degeneration. However, the underlying and related molecular details remain poorly understood. METHODS AND AIM: We review published in vitro and rodent studies of natural products in PD models with the aim to identify common molecular pathways contributing to the treatment efficacy. Commonly regulated genes were identified through the systemic literature search and further analyzed from a network perspective. FINDINGS: Approximately thirty different types of natural products have been investigated for their ability to regulate protein density and gene activity in various experimental systems. Most were found to attenuate neurotoxin-induced regulations. Three common PD pathways are involved. The most studied pathway was neuronal development/anti-apoptosis consisting of Bax/Bcl-2, caspases 3/9, and MAPK signaling. Another well studied was anti-inflammation comprising iNOS, nNOS, Nrf2/ARE, cytokines, TNFα, COX2 and MAPK signaling. The third pathway referred to dopamine transmission modulation with upregulated VMAT2, DAT, NURR1 and GDNF levels. To date, HIPK2, a conserved serine/threonine kinase and transcriptional target of Nrf2 in an anti-apoptosis signaling pathway, is the first protein identified as the direct binding target of a natural product (ZMHC). IMPLICATIONS: Natural products may utilize multiple and intercellular pathways at various steps to prevent DA neurons from degeneration. Molecular delineation of the mechanisms of actions is revealing new, perhaps combinational therapeutic approaches to stop the progression of DA degeneration.


Assuntos
Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Produtos Biológicos/farmacologia , Dopamina/metabolismo , Doença de Parkinson/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Produtos Biológicos/química , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Humanos , Inflamação/tratamento farmacológico , Camundongos , Transmissão Sináptica/efeitos dos fármacos
13.
Biochem Biophys Res Commun ; 513(2): 306-312, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-30954223

RESUMO

Hyposmia occurs during the prodromal phase of Parkinson's disease (PD), while the underlying mechanisms remain unclear. Discussed are altered dopamine content and impairment of neurogenesis of olfactory bulbs (OB), which has been suggested to be linked to olfactory dysfunction. Given that mouse with reduced vesicular monoamine transporter 2 (VMAT2) expression is now deemed as a relatively new PD animal model simulating motor and nonmotor symptoms, it may provide a new insight into investigating the mechanisms of hyposmia in the context of PD. In this study, we examined the effect of subacute administration of MPTP on mice with a reduced expression of VMAT2, focusing on the histopathological and biochemical alterations, specifically, TH expression level, dopamine content as well as neurogenesis in OB. Interestingly, mice with a reduced VMAT2 expression displayed more obvious olfactory impairment in response to MPTP administration accompanied by markedly decreased dopaminergic interneurons in OB. Furthermore, neurogenesis in OB was also further impaired after MPTP due to reduced VMAT2 expression. We therefore demonstrated that reduced expression of VMAT2 contributed to the impairment of hyposmia, pathologically, the degeneration of extranigral systems and reduced neurogenesis might be the underlying mechanisms.


Assuntos
Regulação para Baixo , Doença de Parkinson Secundária/genética , Doença de Parkinson Secundária/fisiopatologia , Proteínas Vesiculares de Transporte de Monoamina/genética , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/patologia , Interneurônios/patologia , Ventrículos Laterais/patologia , Ventrículos Laterais/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Neurogênese , Bulbo Olfatório/patologia , Bulbo Olfatório/fisiopatologia , Doença de Parkinson Secundária/patologia
14.
Front Neurol ; 10: 271, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949126

RESUMO

Although the pathogenic mechanisms of Parkinson's disease (PD) remain unclear, ample empirical evidence suggests that oxidative stress is involved in the pathogenesis of this disease. The nuclear factor E2-related factor 2 (Nrf2) is known to activate several antioxidant response element (ARE)-driven antioxidative genes that prevents oxidative stress in vitro and in vivo. Moreover, it was documented that hydralazine is a potent Nrf2 activator. In this study, we tested whether hydralazine can attenuate 1-Methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- induced neurotoxicity in vitro and in vivo by activating Nrf2 and its downstream network of antioxidative genes. We found that treatment with hydralazine attenuated MPP+ or H2O2-induced loss of cell viability in human neuroblastoma cell line (SH-SY5Y). In addition, hydralazine significantly promoted the nuclear translocation of Nrf2, and upregulated the expression of its downstream antioxidative genes. Further, knockout of Nrf2 abolished the protection conferred by hydralazine on MPP+ -induced cell death. Similar findings were observed in vivo. Before, during, and after MPTP 30 mg/kg (i.p.) administration for 7 days, the mice were given hydralazine (Hyd) 51.7 mg/kg per day by oral gavage for 3 weeks. Oral administration of hydralazine ameliorated oxidative stress, MPTP-induced behavioral disorder, and loss of neurons of dopaminergic system in the substantia nigra (SN) and striatum, all of which were attributed to its ability to activate the Nrf2-ARE pathway. Hydralazine increased the migration of Nrf2 to the nucleus in dopaminergic neurons, enhanced the expression of its downstream antioxidative genes. Together, these datasets show that the Nrf2-ARE pathway mediates the protective effects of hydralazine on Parkinson's disease.

15.
Front Neurol ; 10: 23, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30740086

RESUMO

Cluster headache is generally considered to be a primary headache; secondary cluster-like headache is quite rare, while cluster-like headache secondary to meningioma is even rarer. Here, we describe an unusual case with cluster-like headache 2.5 years after sphenoid ridge meningioma surgery. The cluster-like headache and meningioma were on the same side, and even at the same position. Furthermore, the cluster-like headache lasted for 6 months. In addition, the patient did not respond well to conventional treatments for cluster headache, such as oxygen inhalation, carbamazepine, and tramadol. Brain magnetic resonance imaging demonstrated a softening lesion, glial hyperplasia, and localized thickening and enhancement of the dura in the left frontal-temporal lobe. However, positron-emission computed tomography showed reduced metabolism in the left frontal-temporal lobe. Although the possibility of a primary headache cannot be completely eliminated, the association between cluster-like headache and probable tumor recurrence or postoperative changes should be considered.

16.
Cell Death Dis ; 10(3): 174, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30787269

RESUMO

Recent researches regarding to exosomal involvement in alpha-synuclein (α-syn) transmission relating to the pathological process of Parkinson's disease (PD) have attracted considerable attention. It is highly desirable to make clear the diffusion process and cellular uptake of α-syn-associated exosomes and the underlying mechanism of exosomes-involved communication in the synucleinopathy pathogenesis. To determine the contribution of α-syn-associated exosomes to the initiation and progression of PD, plasma exosomes derived from PD patients were stereotaxically injected into the striatum of mice brains. Exosomes extracted from plasma diagnosed with PD contained monomeric and oligomeric α-syn. Here, we found that microglia display a high potency for uptake of plasma exosomes derived from PD patients, and therefore could be activated by exogenous exosomes in vitro and in vivo. In addition, immunofluorescent double staining verified the transfer of exogenous human exosomal α-syn to neurons. The release of human exosomal α-syn from microglia may facilitate this propagation. Finally, we described a mechanism underlying this potential role of microglia in the transmission of exosomal α-syn. Specifically, exogenous exosomes were found to dysregulate autophagy of the BV2 mouse microglia cell line with presentation of increased accumulation of intracellular α-syn and accelerated secretion of α-syn into extracellular space. These results suggest that microglia play a crucial role in the transmission of α-syn via exosomal pathways, in additional to idea that the progression of PD may be altered by the modulation of exosome secretion and/or microglial states.


Assuntos
Exossomos/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Autofagia , Linhagem Celular , Córtex Cerebelar/metabolismo , Corpo Estriado/metabolismo , Exossomos/ultraestrutura , Feminino , Humanos , Masculino , Camundongos , Microglia/citologia , Pessoa de Meia-Idade , Substância Negra/metabolismo , alfa-Sinucleína/genética
17.
Food Chem ; 275: 197-205, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30724188

RESUMO

To achieve efficient one-step production of gluconic acid, cascade reactions of glucose oxidase (GOD) and catalase (CAT) have been advocated in the biocatalysis system. In this work, the methodology of co-immobilization of GOD and CAT was investigated in details for obtaining improved enzyme loading and activity. The maximum adsorption capability of GOD and CAT was 24.18 and 14.33 mg·g-1, respectively. The matching between dimensions of enzymes and hierarchical pore sizes of carriers are critical to the success of immobilization process. The simultaneous self-assembly on glutaraldehyde cross-linked mesoporous carriers exhibited favorable properties in comparison with sequential immobilization of GOD and CAT. The conversion of glucose under adequate air by co-localized GOD&CAT sustained the activity more than 90% after repeated utilization in the production of sodium gluconate and gluconic acid, suggesting that the co-immobilized GOD&CAT could be a promising catalyst for gluconate and gluconic acid production in some chemical and food industries.


Assuntos
Biotecnologia/métodos , Catalase/química , Enzimas Imobilizadas/química , Gluconatos/metabolismo , Glucose Oxidase/química , Adsorção , Biocatálise , Catalase/metabolismo , Enzimas Imobilizadas/metabolismo , Glucose/metabolismo , Glucose Oxidase/metabolismo , Concentração de Íons de Hidrogênio , Resinas Sintéticas/química
18.
Front Aging Neurosci ; 10: 370, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30524265

RESUMO

Parkinson's disease (PD) is one of the synucleinopathies spectrum of disorders typified by the presence of intraneuronal protein inclusions. It is primarily composed of misfolded and aggregated forms of alpha-synuclein (α-syn), the toxicity of which has been attributed to the transition from an α-helical conformation to a ß-sheetrich structure that polymerizes to form toxic oligomers. This could spread and initiate the formation of "LB-like aggregates," by transcellular mechanisms with seeding and subsequent permissive templating. This hypothesis postulates that α-syn is a prion-like pathological agent and responsible for the progression of Parkinson's pathology. Moreover, the involvement of the inflammatory response in PD pathogenesis has been reported on the excessive microglial activation and production of pro-inflammatory cytokines. At last, we describe several treatment approaches that target the pathogenic α-syn protein, especially the oligomers, which are currently being tested in advanced animal experiments or are already in clinical trials. However, there are current challenges with therapies that target α-syn, for example, difficulties in identifying varying α-syn conformations within different individuals as well as both the cost and need of long-duration large trials.

19.
ACS Omega ; 3(2): 2396-2405, 2018 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30221218

RESUMO

Developing targeted delivery nanosystems for delivering chemotherapeutic anticancer drugs specifically to cancerous tissues with improvement in the specificity of drugs for different cancer cells can result in high therapeutic efficacy and low toxicity in healthy tissues. Herein, we proposed the synthesis of a multifunctional nanodelivery system, folic acid (FA) decorating nanographene oxide (nGO) functionalized with poly(ethylene glycol) (PEG), called pGO-FA, with good biocompatibility and good delivering performance of a hydrophobic water-insoluble anticancer drug of paclitaxel (PTX). 4-br-PEG-NH2, FA, and PTX were attached to PEG-functionalized nGO (pGO) through a combined chemical and physical force to form a nanosized complex, pGO-FA-PTX, defined as the nanodrug system. WST-8 assay in vitro illustrated that pGO-FA-PTX inhibited A2780 cells in a concentration-dependent manner. Cell viability was kept high to 60% when treated with 200 nM of free PTX. However, pGO-FA-PTX with the same dose of PTX (cell viability less than 30%) had double the cytotoxicity effect compared to free PTX. Furthermore, fluorescence observation demonstrated that pGO-FA-PTX exhibited an improved efficiency in killing A2780 cells due to the special affinity between FA and FA receptor, which has high expression in cancer cells. The strategy and method used in this study could be effective in improving both the bioavailability of PTX and therapy efficiency.

20.
Front Aging Neurosci ; 10: 1, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29403371

RESUMO

Parkinson's Disease (PD) is currently considered a systemic neurodegenerative disease manifested with not only motor but also non-motor symptoms. In particular, weight loss and malnutrition, a set of frequently neglected non-motor symptoms, are indeed negatively associated with the life quality of PD patients. Moreover, comorbidity of weight loss and malnutrition may impact disease progression, giving rise to dyskinesia, cognitive decline and orthostatic hypotension, and even resulting in disability and mortality. Nevertheless, the underlying mechanism of weight loss and malnutrition in PD remains obscure and possibly involving multitudinous, exogenous or endogenous, factors. What is more, there still does not exist any weight loss and malnutrition appraision standards and management strategies. Given this, here in this review, we elaborate the weight loss and malnutrition study status in PD and summarize potential determinants and mechanisms as well. In conclusion, we present current knowledge and future prospects of weight loss and malnutrition in the context of PD, aiming to appeal clinicians and researchers to pay a closer attention to this phenomena and enable better management and therapeutic strategies in future clinical practice.

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